This project includes five aims directed to testing hypotheses improving the outcome of allogeneic blood and marrow transplantation. The project addresses innovations to improve the therapeutic index of the preparative regimen, optimize the composition of the allograft and enhance the development of graft versus leukemia while preventing severe graft versus host disease. In Aim 1, we test the hypothesis that durable remissions can be achieved by induction of graft-versus-leukemia as primary treatment for CML and whether this strategy can improve disease free survival. Aim 2 we extend our development of an intravenous formulation of busulfan and test whether a preparative regimen of IV busulfan and cyclophosphamide with dose guiding by pharmacokinetics can improve leukemia free survival for chronic phase patients with matched sibling donors. In Aim 3, we extend our prior studies demonstrating effective GVL induction with CD8 depleted donor lymphocyte infusions and determine the optimal biologic dose for further study with a goal of inducing complete remission with graft- versus-host disease. We will go on to compare their efficacy versus unfractionated lymphocytes for induction of GVL. In Aim 4, we translate innovative approaches being developed in projects 4 and 6 into human clinical trials, testing whether thymidine kinase transduced donor lymphocyte infusions can abrogate GVHD after donor lymphocyte infusions and to evaluate the efficacy of megadose T-cell depleted blood stem cell transplantation for patients with HLA-haploidentical donors. In Aim 5, we will evaluate the efficacy of decitabine as a myelosuppressive agent in preparative regimens for patients with advanced CML and a matched sibling donor.